The invention is concerned with cytoprotective and neuroprotective compounds, which are benzofuran derivatives, said derivatives including steroisomers, mixtures of stereoisomers and therapeutically acceptable salts thereof.
The present invention is concerned with agents providing protection against mitochondrial dysfunction, neuroinflammation, or neurodegeneration. Compositions of the invention are active in certain experimental models that predict efficacy in degenerative diseases in which mitochondrial dysfunction leads to tissue degeneration either directly or indirectly, and in diseases involving neuroinflammation and neurodegeneration. Some of the diseases include, but are not limited to Alzheimer's disease, drug-induced Parkinsonism or Parkinson's disease, Friedreich's ataxia (FRDA) and other ataxias, Leber's hereditary optic neuropathy, epilepsy, and myodegenerative disorders such as MELAS (mitochondrial encephalophaty, lactic acidosis and stroke) and MERRF (myoclonic epilepsy ragged red fiber syndrome).
Compositions of the invention are active in certain experimental models that predict efficacy in, for example, certain ischemic or inflammatory conditions, including but not limited to stroke, myocardial infarction, congestive heart failure, and skin disorders characterized by inflammation or oxidative damage. The invention is therefore related to the use of the cytoprotective derivatives in such conditions.
2,3-Dihydro-5-oxy-4,6,7-trimethyl-2-optionally substituted alkyl benzofurans have been disclosed as antioxidizing pharmaceutical products having anti-ischemic properties in U.S. Pat. No. 5,114,966. Hydroxamine derivatives of 2,3-dihydrobenzofuran carboxy acids have been disclosed in U.S. Pat. No. 5,480,645. 2,3-Dihydrofuran derivatives useful in preventing and treating neovascularization have been disclosed in U.S. Pat. No. 5,719,167 and U.S. Pat. No. 5,798,356. 5-Hydroxybenzofurans have been disclosed for the treatment of a pathological cell proliferative disease in U.S. Pat. No. 5,674,876. A method of inhibiting mammalian leukotriene biosynthesis with 6-hydroxybenzofurans has been disclosed in U.S. Pat. No. 4,714,711.
While various agents have heretofore been provided for such conditions, it has, however, remained desired to provide new therapies for conditions characterized by oxidative stress, and particularly, for providing protection in the event of cerebral ischemia and inflammation; especially desired are agents that are effective even if first administered after a significant period of time (e.g., about 5 or more hours) following an ischemic or oxidative insult.
Furthermore, there is a need for compounds, compositions, and methods that limit or prevent damage to organelles, cells and tissues initiated by various consequences of mitochondrial dysfunction, neuroinflammation or neurodegeneration. Such agents would be suitable for the treatment of degenerative diseases particularly mitochondria associated diseases. The present invention fulfills these needs.